CN116444517A - Carboxamide compound and application thereof in preparation of deubiquitinase USP28 inhibitor - Google Patents

Carboxamide compound and application thereof in preparation of deubiquitinase USP28 inhibitor Download PDF

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CN116444517A
CN116444517A CN202310302003.XA CN202310302003A CN116444517A CN 116444517 A CN116444517 A CN 116444517A CN 202310302003 A CN202310302003 A CN 202310302003A CN 116444517 A CN116444517 A CN 116444517A
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carboxamide compound
usp28
heteroaryl
cancer
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孙元军
韩玉晴
龙亚秋
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Suzhou University
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Abstract

The invention discloses a carboxamide compound and application thereof in preparation of a deubiquitinase USP28 inhibitor. The novel compound has good activity, obvious effect superior to the currently reported USP28 inhibitor, and great expansibility to indications related to USP28, such as cancers, inflammatory diseases, autoimmune diseases, virus infection, cardiovascular diseases and the like, and has bright clinical application prospect.

Description

Carboxamide compound and application thereof in preparation of deubiquitinase USP28 inhibitor
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a carboxamide compound and application thereof in preparation of a deubiquitinase USP28 inhibitor.
Background
USP28 belongs to one of the largest subfamilies among deubiquitinating enzymes (deubiquitylating enzymes, DUBs), a member of USP, and has been found to play an important role not only in the Chk2-p53-PUMA pathway in DNA damage response, but also to stabilize some oncoproteins, such as c-Myc, c-Jun, notch1, cyclin E and HIF-1 a, by antagonizing the function of FBW7, thus exhibiting an effect of promoting tumorigenesis. USP28 has also been found to be overexpressed in a variety of tumor cells, such as non-small cell lung cancer, breast cancer, colon cancer, glioma, and bladder cancer. These biological effects make USP28 a very promising antitumor drug target, especially inhibition of USP28 would probably indirectly inhibit the expression of c-Myc protein, thereby bringing a new idea for targeting the "non-patentable target" of c-Myc.
In 2017, the drug development laboratory of the company of the aslicon discovers the first USP28 inhibitor AZ1 through high-throughput screening, thereby revealing a precursor of the development of the USP28 small molecule inhibitor, and along with the continuous deep research, 4 structural types of USP28 small molecule inhibitors are reported at present, but the activity is poor, and the subsequent biological activity evaluation is also lacking.
Disclosure of Invention
In order to solve the above problems, the present invention provides a carboxamide compound, an optical isomer thereof, and a pharmaceutically acceptable salt or solvate thereof, and an application thereof in preparing a deubiquitinase USP28 inhibitor, and can be used for preparing a medicament for treating cancer, inflammatory diseases, autoimmune diseases, viral infections or cardiovascular diseases.
A first object of the present invention is to provide a carboxamide compound represented by formula I, and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof:
wherein,,
a is a substituted or unsubstituted aryl, heteroaryl or benzoheteroaryl group;
l is one of the structures shown in formula II, wherein n is an integer between 0 and 3,
x is halogen or hydrogen;
Cy 1 is one of the structures shown in formula III:
wherein Ar is a substituted or unsubstituted benzene ring, pyridine ring or pyrimidine ring, and the substituent is independently selected from halogen, aryl, heteroaryl, substituted piperazinyl, morpholinyl, hydroxy and amino.
Further, the heteroaryl, benzoheteroaryl, substituted heteroaryl, or heteroatom on substituted benzoheteroaryl in a is selected from N, O or S atoms.
Further, substituents are independently selected from halogen, aryl, heteroaryl, cyano, hydroxy, amino, trifluoromethyl, C1-C4 straight or branched alkyl, alkoxy.
Further, a substituted aryl, substituted heteroaryl or substituted benzoheteroaryl group contains 1 to 3 substituents.
Preferably, the method comprises the steps of,
a is heteroaryl, substituted heteroaryl or substituted benzoheteroaryl; the heteroatom on the heteroaryl, substituted heteroaryl or substituted benzoheteroaryl is selected from N, O or S atoms; the substituted heteroaryl or substituted benzoheteroaryl contains 1-3 substituents; the substituent groups are independently selected from one or more of halogen, aryl, heteroaryl, cyano, hydroxyl, amino, trifluoromethyl, C1-C4 straight-chain or branched-chain alkyl and alkoxy;
ar is C 5-6 Aryl, heteroaryl consisting of 5-6 ring atoms, wherein the ring is optionally substituted with 1 to 3 substituents, wherein the heteroatoms are selected from N, O or S atoms and the substituents are independently selected from hydroxy, amino.
Further, the compound shown in formula I is selected from one of the following structures:
it is a second object of the present invention to provide a deubiquitinase USP28 inhibitor comprising the above carboxamide compounds and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof.
A third object of the present invention is to provide an antitumor preparation comprising the above carboxamide compound and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof.
A fourth object of the present invention is to provide the use of the above carboxamide compounds and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof for the manufacture of a medicament for the prevention or treatment of diseases related to USP 28.
Further, the disease associated with USP28 is cancer, inflammatory disease, autoimmune disease, viral infection, or cardiovascular disease.
Further, the cancer includes colorectal cancer, lung cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, and the like.
The invention has the beneficial effects that:
the invention provides a carboxamide compound and application thereof in preparing deubiquitinase USP28 inhibitor, and can be used for preparing medicaments for treating cancers, inflammatory diseases, autoimmune diseases, viral infections or cardiovascular diseases. The compound prepared by the invention has excellent performance in USP28 enzyme activity inhibition and anticancer experiments, and the effect of partial structure is obviously better than that of the existing positive medicine, thus having good application prospect.
Drawings
FIG. 1 is the effect of compounds S-1 and S-2 on the expression level of c-Myc protein;
FIG. 2 shows the antitumor effect of compounds S-1 and S-2 in colorectal cancer cell lines.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
The starting materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.
The invention includes the free forms of the compounds of formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof. The free form differs somewhat from its respective salt form in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention such acid or base salts are pharmaceutically comparable to their respective free forms.
In the present invention, carboxamide derivatives may contain one or more asymmetric centers and thus may occur as racemates and single enantiomers, diastereomeric mixtures and single diastereomers. The scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds.
The structure of the compound is changed into a nuclear magnetic resonance structure 1 H-NMR) and/or Mass Spectrometry (MS). NMR measurement was performed using Bruker Advance-400 NMR apparatus with deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD) or deuterated dimethyl sulfoxide (DMSO-d) 6 ) TMS is an internal standard. Waters for MS determination UPLC-mass spectrometer mass spectrometer. The ISCO is used for separating and purifying the product by column chromatographyRf 75 rapid preparative chromatograph, carrier adopts 200-300 mesh silica gel of Qingdao ocean chemical factory, part of final product is purified by thick preparation plate with thickness of 0.4-0.5mm and brand of yellow sea, ultraviolet light color developing box TLC is used for developing color, and all reagents used in synthesis are commercially available without special description.
Example 1 preparation of 1-ethyl-N- (4- ((5, 6,7, 8-tetrahydroisoquinolin-5-yl) amino) phenethyl) -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide (S1)
In the above reaction scheme, the reagents and conditions used are as follows: (a) 5,6,7, 8-tetrahydroisoquinoline, ferric tetrafluoroborate hexahydrate, N-hydroxy-7-azabenzotriazol, oxygen, benzonitrile, 90 ℃; (b)
Tert-butyl [2- (4-aminophenyl) ethyl ] malonate, p-toluenesulfonic acid, toluene, 105 ℃; (c) sodium borohydride, methanol, room temperature; (d) trifluoroacetic acid, dichloromethane, room temperature; (e) 1-ethyl-1H-pyrrolo [2,3-b ] pyridine-5-carboxylic acid, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine, dichloromethane, room temperature. The reaction steps are as follows:
step 1:7, 8-dihydro-isoquinolin-5 (6H) -one
The compound ferric tetrafluoroborate hexahydrate (1.014 g, 3.04 mmol), potassium trispyrazolinyl borohydride (760 mg, 3.04 mmol) and N-hydroxy-7-azabenzotriazol (818 mg, 6.006mmol) were dissolved in 30mL of benzonitrile, and after replacing the air in the reaction flask with oxygen, 5,6,7, 8-tetrahydroisoquinoline (4 g,30.03 mmol) dissolved in 5mL of benzonitrile was added by syringe, and the reaction was heated to 90℃for 50 hours, and the LCMS monitoring the reaction of the starting materials was complete. The reaction solution was directly subjected to silica gel column chromatography (EA: pe=1:10 to 1:6) to give a yellow oil (3.34 g, 76%). 1 H NMR(400MHz,Chloroform-d)δ8.65(t,J＝0.9Hz,1H),8.61(dd,J＝5.1,0.8Hz,1H),7.75(dd,J＝5.0,0.8Hz,1H),2.97(t,J＝6.1Hz,2H),2.73–2.67(m,2H),2.18(tt,J＝6.6,5.5Hz,2H).
Step 2: (E) - (4- ((7, 8-dihydroisoquinolin-5 (6H) -ylidene) amino) phenethyl) carbamic acid tert-butyl ester
Taking 7, 8-Dihydroisoquinolin-5 (6H) -one (1 g,6.803 mmol) and 4- [2- (Boc-amino) ethyl group]Aniline (1.603 g,6.803 mmol) was dissolved in 15mL of toluene, then p-toluene sulfonic acid (120 mg,0.680 mmol) was added, the temperature was raised to 120 ℃ and the reaction was carried out with a water separator, after 1h of reaction, after TLC monitoring the completion of the reaction of the starting material, the reaction solvent was dried by spinning, saturated sodium bicarbonate solution was added, extraction was performed three times with ethyl acetate, washing with saturated brine, the organic phase was collected and dried over anhydrous sodium sulfate, and the yellow solid (733 mg, 30%) was isolated by silica gel column chromatography (1% MeOH/DCM). 1 H NMR(400MHz,Chloroform-d)δ8.54(s,1H),8.07(d,J＝5.2Hz,1H),7.21–7.16(m,2H),7.00–6.96(m,1H),6.77–6.73(m,2H),6.66–6.62(m,1H),3.39(q,J＝6.7Hz,2H),2.90(t,J＝6.1Hz,2H),2.79(t,J＝7.1Hz,2H),2.58(dd,J＝7.2,5.6Hz,2H),1.95(pd,J＝6.3,5.8,2.1Hz,2H),1.44(d,J＝5.3Hz,9H).
Step 3: (4- ((5, 6,7, 8-tetrahydroisoquinolin-5-yl) amino) phenethyl) carbamic acid tert-butyl ester
Tert-butyl (E) - (4- ((7, 8-dihydroisoquinolin-5 (6H) -ylidene) amino) phenethyl) carbamate (700 mg,1.918 mmol) was dissolved in 10mL of anhydrous methanol, then sodium borohydride (145 mg,3.836 mmol) was added in portions and reacted at room temperature for 12H, and TLC monitored the starting material reaction was complete. To the reaction solution was added saturated sodium bicarbonate solution to quench out the remaining sodium borohydride, then a large amount of methanol was swirled off, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate to give a yellow oil (580 mg, 83%). 1 H NMR(400MHz,Chloroform-d)δ8.54(d,J＝5.3Hz,2H),8.08(d,J＝4.7Hz,1H),7.19(d,J＝8.1Hz,2H),6.98(d,J＝8.3Hz,1H),6.78–6.73(m,2H),4.58(s,1H),3.39(d,J＝6.9Hz,2H),2.91(t,J＝6.1Hz,2H),2.79(t,J＝7.0Hz,2H),2.58(dd,J＝7.3,5.6Hz,2H),1.95(dq,J＝7.5,6.3Hz,2H),1.44(s,9H).LCMS(ESI m/z):368.41(M+H).
Step 4: n- (4- (2-aminoethyl) phenyl) -5,6,7, 8-tetrahydroisoquinolin-5-amine
Tert-butyl (4- ((5, 6,7, 8-tetrahydroisoquinolin-5-yl) amino) phenethyl) carbamate (580 mg,1.581 mmol) was dissolved in 10mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the mixture was reacted overnight at room temperature. TLC monitored complete reaction of the starting material, spin-drying of the majority of the dichloromethane and trifluoroacetic acid, extraction of the reaction with dichloromethane and saturated sodium bicarbonate solution, drying over anhydrous sodium sulfate, and thick plate separation (5% methanolic ammonia/dichloromethane) to give a yellow solid (128 mg, 80%). 1 H NMR(400MHz,Chloroform-d)δ8.35(s,1H),8.33(d,J＝5.2Hz,1H),7.32(d,J＝5.1Hz,1H),7.03(dd,J＝8.9,2.6Hz,2H),6.62(dd,J＝8.7,2.4Hz,2H),4.54(t,J＝5.9Hz,1H),3.99–3.82(m,1H),2.91(t,J＝6.8Hz,2H),2.78(dt,J＝8.7,5.9Hz,2H),2.65(t,J＝6.9Hz,2H),2.14–2.03(m,1H),1.98–1.89(m,1H),1.88–1.79(m,2H).
Step 5: 1-ethyl-N- (4- ((5, 6,7, 8-tetrahydroisoquinolin-5-yl) amino) phenethyl) -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide (S1)
N- (4- (2-aminoethyl) phenyl) -5,6,7, 8-tetrahydroisoquinolin-5-amine (50 mg, 0.235 mmol) and 1-ethyl-1H-pyrrolo [2,3-b]Pyridine-5-carboxylic acid (64 mg,0.239 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (100 mg,0.263 mmol) was dissolved in 6mL of dichloromethane, then 120. Mu.L of N, N-diisopropylethylamine was added and reacted overnight at room temperature. After the end of the next day the reaction was dried by spinning, extracted with ethyl acetate and saturated brine, the organic phase was collected and dried over anhydrous sodium sulfate and the thick prep plate was isolated (3.5% MeOH/DCM) as a yellow solid (103 mg, 93%). 1 H NMR(400MHz,Chloroform-d)δ8.64(d,J＝2.0Hz,1H),8.38(d,J＝0.9Hz,1H),8.35(d,J＝5.1Hz,1H),8.32(d,J＝2.1Hz,1H),7.34(d,J＝5.2Hz,1H),7.30(d,J＝3.5Hz,1H),7.10(d,J＝8.4Hz,2H),6.65(d,J＝8.4Hz,2H),6.53(d,J＝3.5Hz,1H),6.16(s,1H),4.57(s,1H),4.36(q,J＝7.3Hz,2H),3.73(q,J＝6.5Hz,2H),2.87(t,J＝6.7Hz,2H),2.80(dt,J＝10.4,6.0Hz,2H),1.49(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ167.18,150.43,148.43,147.34,147.28,145.94,141.75,133.03,129.91,128.98,128.38,127.99,113.45,100.71,53.53,50.98,41.48,39.66,34.87,31.65,28.91,26.17,22.72,19.85,15.69,14.20.LCMS(ESI m/z):526.63(M+H)HRMS(ESI)calcd for C 27 H 26 F 3 N 5 OS[M+H] + ,526.1833；found,526.1833.
Example 2 preparation of 7-amino-3-methyl-N- (4- ((1, 2,3, 4-tetrahydronaphthalen-2-yl) amino) phenethyl) thieno [2,3-b ] pyrazine-6-carboxamide (S2)
In the above reaction scheme, the reagents and conditions used are as follows: a) beta-tetralone, 4- [2- (Boc-amino) -ethyl ] aniline, sodium triacetoxyborohydride, 1, 2-dichloroethane, acetic acid, nitrogen, room temperature; b) Trifluoroacetic acid, dichloromethane, room temperature; c) 7-amino-3-methylthiophene [2,3-b ] pyrazine-6-carboxylic acid, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine, dichloromethane, room temperature. The reaction steps are as follows:
step 1: (4- ((1, 2,3, 4-tetrahydronaphthalen-2-yl) amino) phenethyl) carbamic acid tert-butyl ester
Beta-tetralone (204. Mu.L, 1.53 mmol) and 4- [2- (Boc-amino) -ethyl ]]Aniline (400 mg,1.69 mmol) was dissolved in 12mL of DCE, 1 drop of acetic acid was added, and molecular sieve (80 mg) was stirred at room temperature for 15min. Sodium triacetoxyborohydride (422 mg,2 mmol) was then added and the reaction was allowed to proceed overnight under nitrogen. After the reaction was completed, the reaction solution was extracted with dichloromethane and saturated sodium bicarbonate, and the organic phase was collected and dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (ethyl acetate: petroleum ether=1:10) to give a yellow oil (287 mg, 52%). 1 H NMR(400MHz,Chloroform-d)δ7.11(dt,J＝13.5,4.9Hz,4H),7.01(d,J＝7.9Hz,2H),6.60(d,J＝7.9Hz,2H),4.54(s,1H),3.79(tt,J＝8.6,3.4Hz,1H),3.33(q,J＝6.8Hz,2H),3.22(dd,J＝16.3,4.8Hz,1H),2.92(t,J＝6.6Hz,2H),2.67(d,J＝8.4Hz,2H),2.19(dd,J＝13.1,6.3Hz,1H),2.05(s,1H),1.44(s,9H).
Step 2: n- (4- (2-aminoethyl) phenyl) -1,2,3, 4-tetrahydronaphthalen-2-amine
Tert-butyl (4- ((1, 2,3, 4-tetrahydronaphthalen-2-yl) amino) phenethyl) carbamate (280 mg,0.765 mmol) was dissolved in 5mL of dichloromethane, then 1mL of trifluoroacetic acid was added and reacted overnight at room temperature. The next day, the reaction was extracted with saturated sodium bicarbonate and the organic phase was collected and dried to give a tan solid (210 mg, 75%). 1 H NMR(400MHz,Chloroform-d)δ7.11(dt,J＝13.5,4.9Hz,4H),7.01(d,J＝7.9Hz,2H),6.60(d,J＝7.9Hz,2H),4.54(s,1H),3.79(tt,J＝8.6,3.4Hz,1H),3.33(q,J＝6.8Hz,2H),3.22(dd,J＝16.3,4.8Hz,1H),2.92(t,J＝6.6Hz,2H),2.67(d,J＝8.4Hz,2H),2.19(dd,J＝13.1,6.3Hz,1H),2.05(s,1H).
Step 3: 7-amino-3-methyl-N- (4- ((1, 2,3, 4-tetrahydronaphthalen-2-yl) amino) phenethyl) thieno [2,3-b ] pyrazine-6-carboxamide (S2)
7-amino-3-methylthiophene [2,3-b ]]Pyrazine-6-carboxylic acid (30 mg,0.137 mmol) and N- (4- (2-aminoethyl) phenyl) -1,2,3, 4-tetrahydronaphthalen-2-amine (40 mg,0.15 mmol) were dissolved in 4mL of dichloromethane and then 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (100 mg,0.263 mmol) and 120. Mu.L of N, N-diisopropylethylamine were added and reacted overnight at room temperature. After the completion of the next day reaction, the reaction mixture was dried by spinning, extracted with ethyl acetate and saturated brine, and the organic phase was collected and dried over anhydrous sodium sulfate, and the thick plate was separated (3.5% methanol/dichloromethane) to give a yellow solid (60 mg, 85%). 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.42–7.39(m,1H),7.18(ddd,J＝6.8,4.3,1.9Hz,2H),7.14–7.10(m,1H),7.10–7.05(m,2H),6.65(d,J＝8.4Hz,2H),6.27(s,2H),5.62(t,J＝5.8Hz,1H),4.62(t,J＝5.0Hz,1H),3.90(s,1H),3.64(q,J＝6.6Hz,2H),2.85–2.78(m,4H),2.70(s,3H),1.98(q,J＝5.3Hz,2H),1.26(d,J＝3.9Hz,2H). 13 C NMR(101MHz,DMSO)δ164.34,153.65,152.50,146.26,143.60,141.63,139.18,135.87,135.23,129.13,128.44,126.16,125.63,125.50,112.67,99.65,47.80,41.19,35.60,34.61,28.75,27.54,21.49.LCMS(ESI m/z):458.61(M+H)HRMS(ESI)calcd for C 26 H 27 N 5 OS[M+H] + ,458.1913；found,458.1915.
Following the procedure of examples 1 and 2, the following compounds S3-S24 were prepared, respectively:
EXAMPLE 3 USP28 enzyme Activity inhibition assay
Results of the inhibitory Activity of Compounds of Table 1 on the enzyme Activity of USP28
NA indicates no activity, no activity
Inhibition of USP28 enzyme activity by the compounds of the examples of the present invention: as shown in Table 1, the USP28 enzyme activity inhibitory activities of the compounds of the examples were all on the nanomolar scale, with IC for the vast majority of the compounds 50 Is superior to positive control AZ1. The compound of the embodiment of the patent is shown to retain stronger USP28 enzyme activity inhibition activity.
EXAMPLE 4 SRB assay of Compounds for cell proliferation inhibitory Activity of colorectal cancer cell line Ls174T
Antiproliferative activity of compounds of table 2 on colorectal cancer cell lines with high expression of USP28
Antiproliferative activity of the compounds of the examples of the present invention on the colorectal cancer cell line Ls174T highly expressed by USP 28: as shown in table 2, the compounds of the examples all showed significant antiproliferative activity on colorectal cancer cells Ls174T, wherein the antiproliferative activity of some compounds was superior to that of compound AZ1. In conclusion, the compound of the embodiment of the invention has remarkable anti-tumor cell proliferation effect and is superior to the positive control.
EXAMPLE 5 Western-Blot experiments to determine the Effect of Compounds S-1 and S-2 on the expression level of c-Myc protein
The transcription factor c-Myc plays an extremely important role in the growth, metabolism, tissue development and malignant transformation of cells, and has very important physiological and pathological functions. c-Myc is known to be associated with malignant transformation of tumors and prognosis of survival caused by chronic bacterial infection. Whereas USP28 was found to antagonize FBW7 activity and promote c-Myc stability in cancer cells, inhibition of USP28 would indirectly inhibit c-Myc protein expression.
As shown in FIG. 1, it can be observed from Western-Blot experiments that compounds S-1 and S-2 almost completely inhibited c-Myc expression at 20. Mu.M concentration.
EXAMPLE 6 anti-tumor Effect of Compounds S-1 and S-2 in colorectal cancer cell lines
As shown in FIG. 2, the results of the tumor cell clone formation experiments revealed that the compounds S-1 and S-2 were effective in inhibiting the formation of HCT116 and LS174T cells at 10. Mu.M. These results indicate that compounds S-1 and S-2 are not only effective at inhibiting the deubiquitinase activity of USP28 at the molecular level, but also effective in inhibiting the proliferation and growth of colorectal cancer cells.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations and modifications of the present invention will be apparent to those of ordinary skill in the art in light of the foregoing description. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.

Claims (10)

1. The carboxamide compound shown in formula I and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof, and is characterized in that:
wherein,,
a is a substituted or unsubstituted aryl, heteroaryl or benzoheteroaryl group;
l is one of the structures shown in formula II, wherein n is an integer between 0 and 3,
x is halogen or hydrogen;
Cy 1 is one of the structures shown in formula III:
wherein Ar is a substituted or unsubstituted benzene ring, pyridine ring or pyrimidine ring, and the substituent is independently selected from halogen, aryl, heteroaryl, substituted piperazinyl, morpholinyl, hydroxy and amino.
2. The carboxamide compound as claimed in claim 1, in which: the heteroaryl, benzoheteroaryl, substituted heteroaryl or heteroatom on substituted benzoheteroaryl in a is selected from N, O or S atoms.
3. The carboxamide compound as claimed in claim 2, in which: the substituents are independently selected from halogen, aryl, heteroaryl, cyano, hydroxy, amino, trifluoromethyl, C1-C4 straight or branched alkyl, and alkoxy.
4. The carboxamide compound as claimed in claim 1, in which: substituted aryl, substituted heteroaryl or substituted benzoheteroaryl contain 1-3 substituents.
5. The carboxamide compound as claimed in claim 1, which is characterized in that the compound of formula I is selected from one of the following structures:
6. a deubiquitinase USP28 inhibitor, characterized in that: the deubiquitinase USP28 inhibitor comprising the carboxamide compound as claimed in any one of claims 1 to 5 and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof.
7. An anti-tumor formulation characterized by: the antitumor preparation comprises the carboxamide compound as claimed in any one of claims 1 to 5, and pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof.
8. Use of the carboxamide compounds as claimed in any of claims 1 to 5, as well as the pharmaceutically acceptable salts, racemates, solvates, stereoisomers or polymorphs thereof, for the preparation of a medicament for the prophylaxis or treatment of a disease associated with USP 28.
9. The use according to claim 8, characterized in that: diseases associated with USP28 are cancer, inflammatory diseases, autoimmune diseases, viral infections or cardiovascular diseases.
10. The use according to claim 9, characterized in that: the cancer includes colorectal cancer, lung cancer, breast cancer, glioma, bladder cancer, and pancreatic cancer.
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